Man and other animals have a complex system called the host defense system, or the reticuloendothelium system (RES) for resisting disease. For example, bacteria, parasites, virus particles, neoplastic cells, toxins, antigens, etc., are trapped and destroyed at one or more of the sites of this system. While there are many descriptions and schemes of classification for this system, one widely accepted morphological definition states that the principle components of the host defense system are:
1. The fixed macrophages which monitor the blood stream and are situated in the liver, spleen, bone marrow, and adrenal and pituitary glands:
2. The fixed macrophages which filter the lymph and are present in the sinusoids of lymph glands and follicles;
3. The free macrophages found characteristically in the serous cavities;
4. The fixed histiocytes of the connective tissues;
5. The monocytes of the blood;
6. The microglia of the central nervous system.
It is probable that the lymphocytes and plasma cells also should be included in this system since they certainly participate in recognized host defense functions.
The recognized general functions of this system are phagocytosis, intracellular destruction of alien matter, and antibody formation. To this list one can also add certain specific functions such as specific defense against hemovascular parasites, viruses, bacteria, fungi, tumors, etc.; resistance to shock of various types; hematopoiesis, red cell phagocytosis, and detoxification.
Clearly, if the functions of the host defense could be stimulated, then the host resistance to invasion might well be increased. However, it must be remembered that in some cases stimulation of only one function could have no overall beneficial effect or could even be detrimental. For instance, it is inefficacious to increase the rate of phagocytosis of a pathogen if at the same time greater or faster intracellular destruction cannot occur. Hence, while many substances, both synthetic and natural, can promote an increase in the rate of phagocytosis of invading organisms, few of them promote other host defense functions as well. Such materials have a limited clinical usefulness.
Reviews and articles on substances which stimulate or inhibit the host defense system or its individual subcomponent parts or functions are numerous. One of the earliest of such substances shown to have host defense activity is bacterial endotoxin. This has been the subject of numerous papers. Unfortunately, although it is stimulatory in small doses it is of course lethal in large doses. Before proceeding further it is useful therefore to list the ideal properties that a clinically useable host defense controlling substance should possess. In the case of either a stimulant or an inhibitor.
1. It should affect more than one function or component of the host defense;
2. it must not be toxic;
3. it must not be antigenic;
4. it must not be pyrogenic;
5. it must not cause hyperlasia;
6. it should act in a reasonably low dose;
7. it should produce no untoward side effects.
Many classes of compounds and natural products have been described by various workers as possessing stimulant effects on one or more of the host defense system functions. None of these known materials satisfy the complete criteria cited above for a stimulant or inhibitor useful as a therapeutic agent.
The eventual usefulness of an effective, nontoxic inhibitor of this system in lowering the rejection rate of transplanted organs and tissues may be almost as important as that of a useable stimulant material. The major problem in the post-surgical management of such transplant cases is to maintain the delicate balance in the patient's system between preventing the onset of serious infectious disease and not initiating rejection of the transplanted organ by the host defense system. As present, toxic drugs and/or heavy doses of ionizing radiation are needed to suppress the host defense to prevent transplant rejection. These may cause permanent impairment of the system, resulting in continuing high susceptibility to infectious diseases and, perhaps to neoplastic disease as well. Consequently, transplants of major organs will continue to be a highly hazardous and extremely expensive operation until such time as a nontoxic method of controlling host resistance can be developed for human use.